911³Ô¹Ï

Computational modelling of skeletal muscle protein metabolism and its control    

Skeletal muscle is essential to health and quality of life, with its function closely tied to its mass. Skeletal muscle mass is determined by the balance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB), processes controlled by stimuli such as feeding (e.g., leucine), hormones (e.g., insulin), and resistance exercise. Due to the complexity and multiscale nature of this system, understanding systems-level function in health and disease is challenging using experimental methods and model systems. In my thesis, I developed computational models to study muscle protein metabolism following feeding and exercise.

The protein signalling dynamics following feeding and exercise are typically assessed using semi-quantitative immunoblotting, which identifies the activity of pathways regulating MPS. In Chapter 1, I developed methods for the absolute quantification of protein signalling data, enabling improved accuracy in downstream model development. This method was critical in Chapter 2, where I constructed, validated, and analyzed a kinetic model of leucine-mediated signalling and protein metabolism in the skeletal muscle of healthy adults. A key finding from this work was that the absolute levels of p70 S6 kinase (p70S6K) are a primary determinant of MPS. Consequently, in Chapter 3, I applied a bioinformatics network inference approach to explore the transcriptional regulation of p70S6K protein levels following exercise. This analysis highlighted energy balance pathways, second messenger signalling, and hormonal regulation as key transcriptional controllers of p70S6K levels. In Chapter 4, I used the kinetic model to investigate the multifactorial cause of anabolic resistance in sarcopenia, the age-related loss of muscle mass and function. Anabolic resistance, defined as an impaired MPS response to anabolic stimuli, is a primary driver of sarcopenia. While candidate mechanisms of anabolic resistance have been identified, none singularly acts to reduce MPS. Using sensitivity analysis and simulations of protein metabolism in older adults, I propose that anabolic resistance may arises from the interplay between several mechanisms, some well-established and some less appreciated, which together act to suppress MPS.

Collectively, my PhD research has developed novel computational modelling tools for studying muscle protein metabolism in human skeletal muscle. These models reconcile existing data, provide absolute quantitative estimates, and generate new hypotheses regarding the molecular control of muscle protein metabolism, including the emergence of anabolic resistance. These models offer a foundation for advancing our understanding of muscle protein metabolism and hold promise for informing therapeutic strategies for sarcopenia and other conditions characterized by dysregulated muscle protein metabolism.